Pharmacokinetics of Direct Brain Infusion: Distribution of therapeutic agents in the central nervous system (CNS) with currently available delivery techniques is problematic. An approach that our colleagues and we developed to overcome the obstacles associated with current CNS drug delivery techniques is convective delivery, which uses bulk flow to enhance distribution. Our studies have demonstrated that convection-enhanced delivery to the brain, brainstem, spinal cord, and peripheral nerve in large and small animals can be used to distribute macromolecules in a homogenous, targeted, and safe manner and with clinically effective Vd. Recent efforts have focused on determining the factors that optimize convection-enhanced delivery into the brain, brainstem, spinal cord, and peripheral nerve. To further our understanding of the variables that affect convective delivery we are examining the effect of particle size on distribution in brain, brainstem, spinal cord, and peripheral nerves. High-flow interstitial infusion is being used to deliver various agents, such as immunotoxins, genetic vectors, and chemotherapeutic molecules in the investigation of treatment of various disorders of the central nervous system. We have developed two new imaging contrast agents for non-invasively monitoring infusion volume of distribution and concentration for CT and MRI. Neurotoxicity testing of these imaging agents revealed no evidence of neuronal degeneration up to three months after infusion in rat and primate brains. Thus, we have demonstrated the utility of these imaging agents for real-time, non-invasive monitoring of the distribution of therapeutic agents during infusion of macromolecular drugs. Clinical investigations are planned including direct convective delivery of chemotherapeutic agents to the brainstem for the treatment of brainstem gliomas. Nitric oxide donors for enhancement of drug delivery across the blood - tumor barrier for treatment of CNS tumors: New approaches to enhance drug delivery across the blood-tumor barrier are being investigated. We have demonstrated that the short-acting nitric oxide (NO) donor Proli/NO selectively opens the blood-tumor barrier in rat brain tumors, but not in normal brain, to various-sized radiotracers (up to 70 kD) and does so without significant systemic effects. Proli-NO has been evaluated for its ability to selectively increase the permeability of the blood-tumor barrier to molecules of a wide range of molecular weights over a wide range of doses and infusion regimens. Further studies have been focused on 1) the mechanism of selective action of nitric oxide in tumor endothelial cells (the reason for its selectivity for tumor blood vessels) and 2) the determination of the active compound(s), which induce the permeability changes, indicating that nitrites can be a source of NO. We continue research to elucidate the mechanism of NO-based blood-brain-barrier opening. Convection-enhanced selective excitotoxic ablation of the neurons of the globus pallidus interna for treatment of primate parkinsonism: Selective treatment of central nervous system (CNS) structures holds therapeutic promise for many neurological disorders, including Parkinson's disease (PD). The ability to inhibit or augment specific neuronal populations within the CNS reliably by using present therapeutic techniques is limited. To overcome these problems, we modeled, then developed a method for convective delivery to the CNS which showed that convection- enhanced infusion of an excitotoxin could be used to selectively lesion grey matter regions of the non-human primate brain. To determine the feasibility and clinical efficacy of convective drug delivery for treatment of a neurologic disorder, we selectively ablated globus pallidus interna (Gpi) neurons with an excitotoxin, quinolinic acid (QA), in the 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP)-induced model of primate parkinsonism. Using convection-enhanced delivery to the Gpi, animals were infused with either QA or saline. The three full-parkinsonian animals that underwent Gpi lesioning with QA had substantial improvement of PD symptoms, manifest by a marked increase in activity monitor (AM) activity and dramatic improvement of parkinsonian clinical scores. In contrast, the controls did not improve. Histologic examination revealed selective neuronolysis of Gpi neurons (mean loss = 87%) with sparing of surrounding grey and white matter structures. The properties of convection-enhanced delivery suggest that this method could be used for chemical neurosurgery for medically- refractory PD and that it may be ideal for cell-specific therapeutic ablation or trophic treatment of other targeted structures associated with the CNS disorders. We have submitted a human protocol for convection-enhanced selective excitotoxic lesioning of the Gpi in medically-refractory PD. After success in ablating seizures in an animal model using convective perfusion of the epileptic focus, we are planning a clinical study of the infusion of muscimol, into the hippocampus to temporarily inactivate the neurons of the epileptic focus in patients. If this is successful, we will explore if agents can be used to permanently and selectively inactivate the epileptic focus. As a first step in the project, this year we finished a FDA-required study of the toxicity and distribution of the chronic infusion of muscimol into the hippocampus of 10 non-human primates. The infusions were tolerated without brain injury or permanent adverse effects. The clinical protocol will be initiated after the FDA reviews the data from the animal research study and removes the clinical hold status for the IND. Treatment of cerebral vasospasm after subarachnoid hemorrhage. We have shown that intracarotid infusion of proliNO, a NO donor, reverses and prevents vasospasm after subarachnoid hemorrhage in primates. A clinical protocol to study intracarotid proliNO infusion in patients after aneurysmal SAH has been approved pending additional experimental toxicity data.